The mammalian neocortex is composed of molecularly and functionally distinct projection neurons that facilitate sophisticated cognitive, sensory, and motor abilities. Cortical projection neurons arise from a heterogeneous population of progenitor cells during embryonic development. The generation of specific neuronal subtypes requires the fine orchestration of molecular and cellular events during progenitor proliferation, specification, and differentiation. Anomalies in any one of these processes could lead to neurological disorders. Therefore, a comprehensive study of the mechanistic events that govern these developmental processes is crucial in order to understand the molecular and cellular basis of these diseases. This proposal will investigate how the regulation of Sonic Hedgehog (Shh) signaling pathway affects the specification of cortical progenitor cells into specific projection neuron subtypes. In particular, the role of Suppressor of Fused (Sufu), a critical negative regulator of Shh signaling, will be examined. Preliminary studies show that conditional deletion of Sufu from cortical progenitors early in neurogenesis lead to the abnormal specification of projection neuron subtypes. Based on these initial findings, the primary hypothesis of this proposal is that the tight regulation of Shh signaling by Sufu early in neurogenesis is critical for the specification of cortical progenitors and the specific projection neurons subtypes it will generate. This hypothesis will be tested in the following aims using techniques in histology, confocal microscopy, and signaling/functional protein analyses: Specific Aim 1: Determine how loss of Shh inhibition affects the specification and differentiation of cortical progenitors during embryonic neurogenesis. Specific Aim 2: Determine if inhibition of Shh signaling regulates early generation of cortical progenitors destined to generate upper layer neurons. The applicant, Odessa Yabut, Ph.D., is a postdoctoral scholar who is primarily interested in the mechanisms governing mammalian forebrain development. Dr. Yabut will take advantage of the opportunities offered by the NRSA to gain extensive knowledge in cortical progenitor specification during embryonic development. Dr. Yabut will conduct these studies under the guidance of Samuel Pleasure, M.D., Ph.D., who is an established scientist in the neural development field. With Dr. Pleasure's mentorship, Dr. Yabut will be able to enhance her knowledge on the regulatory mechanisms governing cortical progenitor specification and differentiation, hone her critical thinking skills, and help in her transition towards becoming an independent academic scientist as she develops this project into one that could be the basis of the research to be conducted in her own lab in the future.